J. Org. Chem. 2000, 65, 7747-7749
7747
Selective N-Arylation of Aminobenzanilides under Mild Conditions Using Triarylbismuthanes Roderick J. Sorenson Department of Medicinal Chemistry, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, Michigan 48105 Received April 21, 2000
Diarylamines are prepared selectively in good yields under mild conditions by treatment of aminobenzanilides with triarylbismuthanes in the presence of copper(II) acetate and triethylamine. Arylation under these conditions occurs preferentially at the amino- rather than the amide-nitrogen of the benzanilide. Thus, heating an aminobenzanilide in dichloromethane under reflux in the presence of 1 equiv each of a triarylbismuthane, triethylamine, and copper(II) acetate affords the diarylamine in good yields. This method thereby provides a mild and expeditious route to functionalized diarylamines. Introduction Diarylamines are of considerable importance as synthetic intermediates and as potential therapeutic agents.1 Because anilines are widely available as precursors to this class of compounds, a number of methods have been developed for the arylation of aromatic amino groups. Classical methods for this transformation, typified by the Ullmann-Goldberg condensation,2 often require high temperatures, long reaction times, or other harsh or stringent conditions incompatible with many functional groups. Accordingly, novel protocols have been developed to address these limitations. The research groups of Buchwald3 and Hartwig4 utilized palladium to catalyze the amination of aryl halides. Barton and co-workers introduced triarylbismuthanes5 and organolead derivatives6 for the N-arylation of anilines. Chan and coworkers subsequently demonstrated the use of organobismuth(III) reagents for the N-arylation of amides and amide-like moieties.7 Finet and Combes8 have continued to exploit the reactivity of triarylbismuth(V) reagents for arylation reactions. We have previously described a method for the N-phenylation of anilines bearing a wide variety of functional groups utilizing triphenylbismuthane under very mild conditions.9 We herein report an (1) (a) Buchwald, S. L.; Harris, M. C.; Geis, O. J. Org. Chem. 1999, 64, 6019-6022. (b) Sawyer, J. S.; Schmittling, E. A. J. Org. Chem. 1993, 58, 3229-3230, and references therein. (2) (a) Lindley, J. Tetrahedron 1984, 40, 1433-1456. (b) Kaltenbronn, J. S.; Scherrer, R. A.; Short, F. W.; Jones, E. M.; Beatty, H. R.; Saka, M. M.; Winder, C. V.; Wax, J.; Williamson, W. R. N. Arzneim.Forsch. 1983, 33, 621-627. (c) Hebky, J.; Radek, O.; Kejha, J. Collect. Czech. Chem. Commun. 1958, 3988-39. (d) Galy, J.-P.; Hanoun, J.P.; Tenaglia, A. Synth. Commun. 1995, 25, 2443-2448. (e) Pellon, R. F.; Carrasco, R.; Rodes, L. Synth. Commun. 1996, 26, 3869-3876. (3) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805-818. (b) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722-9723. (4) (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046-2067. (b) Hartwig, J. F.; Dawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575-5580. (5) Barton, D. H. R.; Finet, J.-P.; Khamsi, J. Tetrahedron Lett. 1987, 28, 887-890. For a review of organobismuth applications, see: (a) Suzuki, H.; Ikegami, T.; Matano, Y. Synthesis 1997, 249-267. (b) Finet, J. P. Chem. Rev. 1989, 89, 1487-1501. (c) Abramovitch, R. A.; Barton, D. H. R.; Finet, J. P. Tetrahedron 1988, 44, 3039-3071. (6) Barton, D. H. R.; Yadav-Bhatnagar, N.; Finet, J.-P.; Khamsi, J. Tetrahedron Lett. 1987, 28, 3111-3114. (7) Chan, D. M. T. Tetrahedron Lett. 1996, 37, 9013-9016. (8) Finet, J.-P.; Combes, S. Tetrahedron 1998, 54, 4313-4318.
extension of this approach in which the amino nitrogen of a benzanilide is selectively arylated while the amide functionality is preserved unchanged. Results and Discussion Confronted with a need for the expedient preparation of a series of diarylamines, and drawing upon previous research in this area, we were prompted to explore the reaction of organobismuth(III) reagents with functionalized aminobenzanilides. In the presence of a basic promoter, arylation was observed to occur exclusively at the amino nitrogen rather than the amide nitrogen of the substrates, thus providing a novel route to the desired class of compounds. This result is surprising in that Chan et al.7 had originally developed this modification of the Barton procedure expressly for the purpose of arylating amide nitrogens. Even so, in most cases throughout our investigation no evidence was found for the production of any bis- or tris-adducts. Accordingly, a large number of diarylamines were prepared using this procedure. Representative examples are shown in Table 1. Both electron-withdrawing and electron-donating groups were tolerated in either the substrate or the triarylbismuthane. In some examples small amounts of unidentified byproducts were observed. These were easily removed by recrystallization or column chromatography. The required triarylbismuthanes were readily obtained via a simple procedure in which the corresponding Grignard or aryllithium reagents were allowed to react with bismuth(III) halide.10 These reagents are usually crystalline, easy to purify, and exhibit low reactivity toward moisture and oxygen so that multigram quantities can be prepared and stored for prolonged periods. The anilines were either commercially available or readily synthesized using standard methods. 3-Amino4-fluoro-N-(3,4-difluorophenyl)benzamide (Table 1, entry (9) Sorenson, R. J. N-Arylations with triphenylbismuthane. Book of Abstracts; 218th ACS National Meeting, New Orleans, LA, Aug 2226, 1999; American Chemical Society: Washington, D.C.; ORGN-523. (10) (a) Banfi, A.; Bartoletti, M.; Bellora, E.; Bignotti, M.; Turconi, M. Synthesis 1994, 775-776. (b) Klaveness, J.; Berg, A.; Almen, T.; Golman, K.; Droege, M.; Yu, S. WO96/22994, Issued: August 1, 1996. (c) For a review see Freedman, L. D.; Doak, G. O. Chem. Rev. 1982, 82, 15-57.
10.1021/jo000614m CCC: $19.00 © 2000 American Chemical Society Published on Web 10/21/2000
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J. Org. Chem., Vol. 65, No. 23, 2000
Sorenson
Table 1. Selective N-Arylation of 3-Aminobenzanilidesa,b
entry
R1
R2
R3
1 2 3 4 5 6 7 8 9 10 11 12 13 14
H 4-OMe 4-OMe 4-OMe 4-OMe 4-OMe 4-OMe 4-OMe 4-F 4-Cl 2-F 4-SMe 4-OCF3 4-OMe
H H H 2-OMe 3,4-di-F H H H 3,4-di-F H H H 4-F 4-CO2Me
H H H H 3-OBn 2-OMe 3-Cl 3,5-di-Me 3-CF3 H 3-CF3 3-CF3 3-CF3 3-CF3
Table 2. N-Arylation of Aminobenzamidesa,b
compd isolated yield (%) 1 2 2 3 4 5 6 7 8 9 10 11 12 13
94 74 0c 85 81 81 82 51 74 77 90 46 48 90
a Satisfactory 1H NMR, CIMS, and microanalyses were obtained for all substrates and products. b 1.0 equiv of substrate, 1.05 equiv each of Ar3Bi, Cu(OAc)2, TEA in CH2Cl2; reflux; 3-20 h. cNo TEA added.
9), for example, was prepared from 3-nitro-4-fluorobenzoic acid by formation of the acid chloride, reaction with 3,4-difluoroaniline, and subsequent catalytic reduction of the nitro group.11 This method is remarkable for the mild conditions required. Many of the arylations proceeded readily at room temperature, though the time required to attain completion was considerably shortened by heating under reflux in dichloromethane. Tetrahydrofuran is also a suitable solvent for the reaction, but in some experiments its use resulted in a small amount of bis-arylation. Palladium-catalyzed methodologies developed for the amination of aryl halides,12 even when performed at room temperature, often require the use a strong base that may not be compatible with sensitive substrates. In contrast, the method described here utilizes only triethylamine as a promoter. Barton et al.5 were able to achieve the formation of diarylamines without a promoter, but in a control experiment in which triethylamine was omitted (Table 1, entry 3) we were unable to push the chemoselective reaction to completion, despite prolonged heating under reflux. An inert atmosphere was not required during the reaction: protection from atmospheric moisture was sufficient. An experiment in which 1 equiv of water was deliberately introduced to the reaction mixture resulted in consumption of the organobismuth reagent without concomitant appearance of product, even after another (11) Connor, D. T.; Roark, W. H.; Sexton, K.; Sorenson, R. J. WO 9932433, 1999. (12) (a) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 6054-6058. (b) Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997, 38, 4807-4810. (c) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617-620. (d) Yamamoto, T.; Nishiyama, M.; Koie, Y. Tetrahedron Lett. 1998, 39, 2367-2370. (e) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369-7370. (13) Legrand, L.; Lozac’h, N. Bull. Soc. Chim. Fr. 1973, (Part 2), 1665-1667.
a Satisfactory 1H NMR, CIMS, and microanalyses were obtained for all substrates and products. b 1.0 equiv of substrate, 1.05 equiv each of Ar3Bi, Cu(OAc)2, TEA in CH2Cl2; room temp; 20 h. c See ref 13.
1 equiv of the bismuth reagent was added. When an inert atmosphere was maintained, it was in some cases necessary to add a small additional amount of copper(II) acetate after several hours to obtain full conversion of the starting material. The effect of oxygen on the reaction has been previously described.5 Table 2 illustrates the generalization of this method to a broader array of substrates, including those in which the relationship of the substituents is less favorable, as in entries 1 and 2. Chemoselectivity is realized even when the amino group of the benzanilide is part of a vinylogous amide. A limitation was encountered when a primary amide was selected as the substrate, as shown in entry 3. In this case a complex mixture of products was obtained, from which previously characterized benzanilide 2 (6% yield) was the only product isolated. This limitation was not attributable to the selectivity being specific to Narylbenzamides, however, as N-cyclopropyl and N-methyl analogues 20 and 22 were the only detectable products of the arylation reaction shown in entries 4 and 5. A minor drawback to this method is that only one of the aryl groups of the bismuth reagent is transferred to
Selective N-Arylation of Aminobenzanilides
the substrate, and this may be a disadvantage in the case of more elaborate aryl groups. Another consideration is that the copper salt is required in stoichiometric amounts, and its disposal may become a concern as the scale of the reaction is increased. Since arylations using bismuth(V) reagents are known to be catalytic in copper,5 we are currently investigating the selectivity of these conditions. In summary, we have developed a practical and versatile method for the selective N-arylation of amino groups in functionalized aminobenzanilides that proceeds under mild conditions using readily available, easily handled reagents.
Experimental Section General Methods. Melting points are uncorrected. The 1H NMR spectra were recorded at 400 MHz in DMSO-d6. Chemical shifts are reported in ppm (δ) and referenced to the residual proton signal for DMSO-d6 (2.49 ppm). The coupling constants (J) are reported in hertz. Elemental analyses were performed by Quantitative Technologies Inc. and were within 0.4% of theory. Reagents were obtained from commercial sources and used without additional purification. Reaction progress was monitored using EM Science precoated silica gel 60 F254 thinlayer chromatography plates, eluting with CHCl3/EtOAc 9:1. Biotage prepacked silica gel columns were used for chromatographic purifications. Materials. Substrates for Table 1, entries 1-3, 6-8, 10, and Table 2, entries 1 and 2, were obtained from Apin Chemicals Ltd. Benzamide 18 was obtained from Pfaltz & Bauer, Inc. Substrates for Table 1, entries 5, 11, 12, and 13 were prepared according to published procedures.11 Substrates for Table 1, entries 4 and 14 were prepared analogously to that for Table 1, entry 8 (see Supporting Information for data). Triphenylbismuthane was obtained from Alfa Aesar. The preparation of tris(3-chlorophenyl)bismuthane and tris(3trifluoromethylphenyl)bismuthane is described in the literature.10 Tris(3,5-dimethylphenyl)bismuthane and tris(3-benzyl-
J. Org. Chem., Vol. 65, No. 23, 2000 7749 oxy-phenyl)bismuthane were obtained similarly (see Supporting Information, compounds 23 and 24). Tris(2-methoxyphenyl)bismuthane is commercially available from Aldrich Chemical Co. Solvents were used without prior drying. Representative Procedure for the Arylation Reaction. (3-(3-Chlorophenylamino)-4-methoxy-N-phenylbenzamide (6). Copper(II) acetate (1.16 g, 6.4 mmol) was added to a stirred mixture of 3-amino-4-methoxy-N-phenylbenzamide (1.5 g, 6.2 mmol), tris(3-chlorophenyl)bismuthane (3.5 g, 6.4 mmol), and triethylamine (0.65 g, 6.4 mmol) in dichloromethane (120 mL), and the mixture was heated to reflux. After 4 h, heating was discontinued and the mixture diluted with additional dichloromethane (150 mL) and stirred into 2 N hydrochloric acid (200 mL). After 2 h, the layers were separated, and the organic phase was washed successively with 2 N HCl, water, 0.5 M aqueous potassium carbonate, water, and saturated aqueous sodium chloride and then dried over MgSO4. The solution was filtered and then stripped of solvent under reduced pressure. The residue was chromatographed on a column of silica gel in chloroform/ethyl acetate (99:1) to afford the product (1.8 g, 82% yield): mp 163-165 °C. A sample was recrystallized from ethanol to give pure 6 as glittering white scales: mp 168-170 °C; IR (KBr, cm-1) 3395, 3322, 1647, 1589, 1519, 1245, 758; 1H NMR (DMSO) δ 10.02 (s, 1H), 7.80 (d, J ) 8.8 Hz, 2H), 7.68 (d, J ) 7.6 Hz, 2H), 7.62 (d, J ) 8.5 Hz, 1H), 7.27 (dd, J ) 7.9 Hz, 2H), 7.13 (m, 2H), 7.02 (t, J ) 7.3 Hz, 1H), 6.94 (m, 2H), 6.75 (d, J ) 7.8 Hz, 1H), 3.84 (s, 3H); MS (APCI), m/z 353.0, 355.0 (M+ + 1). Anal. Calcd for C20H17ClN2O2: C, 68.09; H, 4.86; N, 7.94. Found: C, 67.91; H, 4.71; N, 7.80.
Acknowledgment. The author is indebted to Drs. David T. Connor and Jie Jack Li for helpful discussions. Supporting Information Available: 1H NMR for all substrates, triarylbismuthanes, and products; microanalyses and melting points for all products. This material is available free of charge via the Internet at http://pubs.acs.org. JO000614M
